This application is for a predoctoral fellowship awarded by the National Institute of Allergy and Infectious Diseases to physician-scientist trainees. The applicant is a Medical Scientist Training Program trainee at the Perelman School of Medicine at the University of Pennsylvania and would be assisted by this award in achieving his career goals of becoming a physician-scientist in the field of Infectious Diseases. Novel immune responses identified in human and nonhuman primate models of HIV and SIV infection have invigorated the field of AIDS vaccine research, even in the wake of disappointing clinical trial outcomes. Reported in this F30 application is the discovery of a novel immune response against peptides encoded by the HIV-1 5' leader RNA sequence. These findings come as a surprise because the HIV-1 5' leader, which contains numerous regulatory elements encoded in its RNA secondary structure, has been thought to be translationally silent. Preliminary data suggest just the opposite, that the 5' leader encodes immunogenic peptides that drive the development of potent cellular immune responses. The applicant postulates that these newly discovered immune responses may play a role in virus containment because viral escape mutations in conserved RNA structures would be expected to impose significant costs to viral replicative fitness. The current proposal will test this hypothesis. In Aim I, the applicant proposs a systematic analysis of 5' leader peptide (5LP) expression and anti-5LP targeted cellular immune responses in 20 HIV-1 infected humans. In Aim 2, the applicant proposes to investigate 5LPs as potential vaccine immunogens by studying viral fitness costs resulting from viral mutational escape from anti-5LP responses and the antigenic cross-reactivity of 5LPs within and among different HIV-1 subtypes. Most of the preliminary work leading to the present proposal has been conducted in a small number of HIV-1 infected human subjects and in SIVmac239 infected Indian rhesus macaques. This application represents the first systematic analysis of 5LP targeted immune responses in a robust number of human subjects that will allow for general conclusions to be reached regarding role of these responses in virus-host immunopathogenesis and potentially in vaccine development.